The LDL-receptor related protein 1 (LRP1) is a highly efficient endocytic and a signal transducing receptor that plays an important role in vascular development. By developing a mouse in which LRP1 was genetically deleted in vascular smooth muscle cells (SMC), we have also discovered that LRP1 protects the vasculature from the development of aneurysms. Currently, mechanisms by which this occurs are not well understood, but our studies thus far reveal that LRP1 regulates matrix assembly, TGF? signaling, and levels of protease activity in the vessel wall. Defining the molecular mechanism by which LRP1 regulates these events is one goal of this Outstanding Investigator Award. The significance of these studies are enhanced by the identification of patients with aneurysmal disease harboring missense mutations in LRP1. Biochemical characterization of the functional defects imposed by these mutant receptors will be critical to define the mechanisms by which LRP1 regulates vessel wall homeostasis, and represents another major goal of our studies. This will be accomplished by a the generation of mutant LRP1 substituted mice employing the CRISPR/Cas9 system. LRP1 interacts with over 40 ligands with high affinity, and despite substantial effort, very little information is available regarding the nature of the receptor/ligand complex. We also propose strategies to solve this problem using the latest technological advances in structural biology. Closely related in structure to LRP1 is LRP1B, another receptor that is abundant in SMC and regulates their migration and proliferation by unknown mechanisms. We propose genetic, proteomic and RNA-seq analysis to identify mechanisms by which this receptor regulates SMC growth. Together, the studies will define the mechanisms by which LDL receptor family members protect the vasculature from disease and may identify novel therapeutic approaches for patients harboring LRP1 missense mutations.